Vagus Nerve Stimulation-Induced Laryngeal Motor Evoked Potentials: A Possible Biomarker of Effective Nerve Activation

Abstract

Vagus nerve stimulation (VNS) therapy is associated with laryngeal muscle activation and induces voice modifications, well-known side effects of the therapy resulting from co-activation of the recurrent laryngeal nerve. In this study, we describe the non-invasive transcutaneous recording of laryngeal motor evoked potentials (LMEPs), which could serve as a biomarker of effective nerve activation and individual titration in patients with drug-resistant epilepsy. We recruited drug-resistant epileptic patients treated for at least 6 months with a VNS. Trains of 600-1200 VNS pulses were delivered with increasing current outputs. We placed six skin electrodes on the ventral surface of the neck, in order to record LMEPs whenever the laryngeal muscular threshold was reached. We studied the internal consistency and the variability of LMEP recordings, and compared different methods for amplitude calculation. Recruitment curves were built based on the stimulus-response relationship. We also determined the electrical axis of the LMEPs dipole in order to define the optimal electrode placement for LMEPs recording in a clinical setting. LMEPs were successfully recorded in 11/11 patients. The LMEPs threshold ranged from 0.25 to 1 mA (median 0.50 mA), and onset latency was between 5.37 and 8.77 ms. The signal-to-noise ratio was outstanding in 10/11 patients. In these cases, excellent reliability (Intraclass correlation coefficient, ICC > 0.90 across three different amplitude measurements) was achieved with 10 sample averages. Moreover, our recordings showed very good internal consistency (Cronbach's alpha > 0.95 for 10 epochs). Area-under-the-curve and peak-to-peak measurement proved to be complementary methods for amplitude calculation. Finally, we determined that an optimal derivation requires only two recording electrodes, aligned on a horizontal axis around the laryngeal prominence. In conclusion, we describe here an optimal methodology for the recording of VNS-induced motor evoked responses from the larynx. Although further clinical validation is still necessary, LMEPs might be useful as a non-invasive marker of effective nerve activation, and as an aid for the clinician to perform a more rational titration of VNS parameters.

Keywords: biomarkers; electrical axis; epilepsy; internal consistency; larynx; motor evoked potentials; reliability; vagus nerve stimulation (VNS).

FIGURE 1

(A) Schematic representation of the recording surface electrode placement. EH+/EH– electrodes were aligned horizontally, and placed symmetrically on each side of the laryngeal prominence, at half the distance between the midline and the medial edge of the sternocleidomastoid muscle (approximately 4 cm). EV+/EV– electrodes were aligned vertically, placed on the midline 6 cm above and below the laryngeal prominence. Additionally, two electrodes for artifact recording (Art1–Art2) were placed on the left mastoid and below the left clavicle side of the neck (not shown in figure), and one grounding electrode was placed on the forehead (not shown in figure). The distances take into account an approximation due to the curvature of the neck and due to the perspective of the image. (B) Scheme of the stimulation protocol.

FIGURE 2

An example of LMEP and its characteristics, as displayed in a 28 ms epoch. The different measurements for amplitude that were are studied are indicated: area-under-the-curve (AUC), peak-to-peak (P2P), and N1 prominence.

FIGURE 3

Example of LMEP single epochs, in patients with a good signal-to-noise ratio (SNR) and sampling rate at 32 kHz. (A) Intra-patient reproducibility (PAT 1), in different trains at increasing current output. (B) LMEPs recorded across different patients, at their respective normal current output (1–1.75 mA). Variation of amplitudes and latencies can be appreciated. Latencies are comprised in a 5.4–8.7 ms range (mean: 6.89 ms). PAT 2 is not shown due to a sampling rate of 2048 Hz that hampers a meaningful overlay. PAT 5 is not shown due to low SNR.

FIGURE 4

Internal consistency of LMEPs, in the case of good SNR. (A) LMEP recordings recorded from PAT 4. At the top of the figure, overlay of maximal amount of 1200 LMEPs. In the middle, overlay of randomly chosen 20 LMEPs. At the bottom, overlay of the averages from 1200 (blue line) and 20 curves (orange line), showing excellent robustness (Pearson’s coefficient > 0.95). (B) Values of Cronbach’s alpha for the peak-to-peak (P2P), area-under-the-curve (AUC) and N1 prominence amplitude calculation, at increasing number of curves included in the trial count. (C) Pearson’s correlation coefficient between LMEP amplitude results for small-number averages with those obtained at grand average.

FIGURE 5

Laryngeal motor evoked potentials (LMEPs) recorded from PAT 5, which was the only patient with low signal-to-noise ratio. Comparison of average parameters at increasing number of epochs (10, 20, 50, 100, 200, maximum). (A) Consecutive odd-numbered single epochs were overlaid and averaged (blue color) and compared to consecutive even-numbered epochs (orange color). (B) Averaged curves were compared between them, with an increasing consistency of the curves across the two subgroups. Amplitude measurements become highly consistent as the number of epochs included in the average reaches 100 curves (Pearson correlation > 0.90).

FIGURE 6

Recruitment curve of LMEP amplitude (peak-to-peak values) visualized by linear interpolation.

FIGURE 7

Electrical axis of LMEP dipole (D_LMEP). A vector directed toward 0° means a horizontal vector directed to the right. A vector directed toward 90° means a vertical vector directed cranially. Single-patient (gray) and mean values (red) are displayed.

FIGURE 8

Comparison of LMEP recording with EH electrodes placed at 2, 4, and 6 cm laterally to the laryngeal prominence. The stimulation was performed at 1.75 mA of current output (Xstim). The bright red lines represent the averaged curve for each train. Muscular artifacts are more visible when 6 cm distance is used for the recording.